Pharmaceutically acceptable salts of quinolinone compounds having improved pharmaceutical properties

Abstract

A lacate salt of a compound of Formula I or a tautomer of the compound, wherein Formula I has the following structure and R 1 -R 9 and R 12 -R 14 are as defined herein

1 . A lactate salt of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one. 
     
     
         2 . The lactate salt of  claim 1 , wherein the salt comprises the mono-lactate or bis-lactate salt. 
     
     
         3 . The lactate salt of  claim 1 , wherein the salt comprises the mono-lactate salt. 
     
     
         4 . The lactate salt of  claim 1 , wherein the solubility of the salt in water at 22° C. is greater than 30 mg/mL. 
     
     
         5 . The lactate salt of  claim 1 , wherein the solubility of the salt in water at 22° C. is from about 150 mg/mL to about 250 mg/mL. 
     
     
         6 . The lactate salt of  claim 1 , wherein the salt comprises the DL lactate salt. 
     
     
         7 . The lactate salt of  claim 1 , wherein the salt comprises the D lactate salt. 
     
     
         8 . The lactate salt of  claim 1 , wherein the salt comprises the L lactate salt. 
     
     
         9 . The lactate salt of  claim 1 , wherein the salt comprises the D lactate salt, the L lactate salt, or a mixture thereof. 
     
     
         10 . The lactate salt of  claim 1 , wherein the salt comprises plate-shaped crystals. 
     
     
         11 . A composition comprising a tablet of the lactate salt of  claim 1 . 
     
     
         12 . A method of preparing the lactate salt of  claim 1 , comprising:
 (a) Suspending 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one in a solvent or mixture of solvents;   (b) Contacting lactic acid with 4-amino-5-fluoro-3-[6-(4-methylpiperzain-1-O-1H-benzimidazol-2-yl]quinolin-2(1H)-one to provide a mixture;   (c) Heating the mixture;   (d) Cooling the mixture; and   (e) Isolating the salt.   
     
     
         13 . The method of  claim 12 , wherein the solvent is a protic solvent. 
     
     
         14 . The method of  claim 12 , wherein the solvent is selected from the group consisting of methanol, ethanol, water, tetrahydrofuran, and mixtures thereof. 
     
     
         15 . A pharmaceutical formulation, comprising the lactate salt of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         16 . A crystalline lactate salt of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-3(1H)-one, wherein the solubility of the salt in water at 22° C. is from about 100 mg/mL to about 400 mg/mL.